The present invention relates to the neurofibromatosis type 1 (NF1) gene and its gene product. The invention further relates to methods for the detection and treatment of humans having defective NF1 genes.
The publications and other materials used herein to illuminate the background of the invention and in particular cases to provide additional details respecting its practice are incorporated by reference and for convenience are numerically referenced in the following text and respectively grouped in the appended bibliography.
The neurofibromatoses are genetic disorders that primarily affect cell growth of neural tissues. These disorders can cause tumors to grow on the nerves at any location and at any time. Some manifestations are progressive, and may result in significant morbidity or mortality. Two distinctive forms are recognized, but variant forms may exist.
The most common type, neurofibromatosis type 1 or NF1 (previously known as von Recklinghausen's neurofibromatosis or peripheral neurofibromatosis), is an autosomal dominant disorder affecting about 1 in 3500 individuals (1).
The spontaneous mutation rate is quite high, with 30%-50% of NF1 affected individuals representing new mutations. This leads to a calculated mutation rate of about 1/10,000, which is about 100-fold higher than the usual mutation rate for a single locus. One explanation for such a high mutation rate is that the NF1 gene is a megagene analogous to the Duchenne muscular dystrophy gene.
The clinical features of the disorder are startlingly variable, even within the same family, indicating that other events must play a role in the eventual phenotype of the disease. The diagnostic criteria for NF1 include the presence of two or more of the following: (1) six or more cafe-au-lait macules more than 15 mm in greatest diameter in postpubertal individuals, or 5 mm in prepubertal individuals; (2) two or more neurofibromas of any type, or one plexiform neurofibroma; (3) freckling in the axillary or inguinal regions; (4) optic glioma; (5) two or more Lisch nodules (iris hamartomas); (6) a distinctive bony lesion such as sphenoid dysplasia or thinning of long-bone cortex, with or without pseudoarthrosis; (7) a first-degree relative with NF1 (1). The penetrance of NF1 is extremely high if individuals are carefully examined, including the use of a slit-lamp to detect Lisch nodules. Under those circumstances, it is rare to identify an adult obligate gene carrier who does not meet the criteria listed above (2).
Mapping of the NF1 gene to human chromosome 17q has involved the use of linkage analysis on NF1 families (3-5) and physical mapping using somatic cell hybrids and pulsed-field gel electrophoresis (PFGE) (6-8). Two NF1 translocation have been identified within 17q11.2, t(1;17) and t(17;22) (9,7). The portion of chromosome 17 containing these translocations has sometimes been referred to as the translation breakpoint region (TBR). Although significant progress has been made in mapping the NF1 gene, the gene has not been identified, cloned or sequenced prior to the present invention.